The causal factors in neonatal Respiratory Distress Syndrome, RDS, are insufficient production and presence of surfactant in the developing lungs of babies born prematurely. This deficit results in markedly impaired respiratory function that not only causes a high mortality but leads to respiratory complications throughout childhood and into adult life. Our goal is to change the paradigm of surfactant therapy in babies born prematurely and in so doing improve their survival and reduce the associated chronic lung problems. Of the 15 million premature babies born around the world, one million will die annually within the first month of life, and many of the 14 million survivors are faced with a lifetime of serious health complications. Respiratory distress syndrome, RDS, is the single most important cause of mortality and morbidity in preterm infants. Both surfactant instillation into the lungs and continuous positive airway pressure, CPAP, have been shown to improve outcomes in premature babies with RDS. However, the complication rate, comorbidities and mortality rate due encountered due to the need for intubation to instill surfactant remain high in spontaneously breathing premature babies remains high. To mitigate these adverse sequelae, this proposal focuses on the development of non-invasive aerosol surfactant replacement therapy. Namely, the delivery of ?2 m MMAD pure surfactant aerosol that deposits in the peripheral regions of the neonatal lungs. The major issue inhibiting the realization of a successful therapy has been the inability to reliably deliver a therapeutically relevant mass of surfactant to the peripheral lung in an acceptably short treatment time. Compared to an aqueous aerosol generated from a 35 mg/ml surfactant suspension, a similar sized pure solid- phase fine particle surfactant aerosol delivers 30 times the dose. When pure surfactant aerosols are produced from higher concentrations of surfactant suspensions together with higher atomization rates and delivered as pure solid-phase aerosols, even higher delivery rates are achievable. In addition, when the pure solid phase aerosol is less than ?2 m MMAD losses related to the delivery of the aerosol are minimized together with greater peripheral deposition improved efficacy can be obtained within a shorter treatment time. A game-changing system for aerosol surfactant replacement therapy that overcomes present limitations of mesh nebulizers and jet atomizers is proposed, SUPRAER-Mini. An aerosol is generated from an aqueous surfactant suspension, the water is rapidly evaporated from the suspended droplets and the resulting surfactant aerosol concentrated using a virtual impactor. This proposal is targeted at demonstrating that using such an aerosol generation and processing system and an integrated with an aerosol-friendly interface, high concentrations of ?2m MMAD surfactant aerosols with narrow size distributions can be delivered at 3l/min to 6 l/min. The aerosols will be delivered at under conditions of CPAP at an absolute humidity of 10-15 mg/l. The performance of the aerosol processing system, the device interface, and the effectiveness of this aerosol generation and processing system will be evaluated on the bench. The physiological responses of surfactant aerosol delivery will be demonstrated in a spontaneously breathing lavage-induced rabbit model of respiratory distress.